Design and synthesis of potent amido- and benzyl-substituted cis-3-amino-4-(2-cyanopyrrolidide)pyrrolidinyl DPP-IV inhibitors

The cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of 5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor 53 exhibited a prefer...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-12, Vol.17 (24), p.6707-6713
Main Authors: Corbett, J.W., Dirico, K., Song, W., Boscoe, B.P., Doran, S.D., Boyer, D., Qiu, X., Ammirati, M., VanVolkenburg, M.A., McPherson, R.K., Parker, J.C., Cox, E.D.
Format: Article
Language:English
Subjects:
Amination
Animals
Benzene - chemistry
Biological and medical sciences
Cyanides - chemistry
Diabetes
Dipeptidyl Peptidase 4 - chemistry
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl peptidase IV
Dipeptidyl-Peptidase IV Inhibitors
Dogs
DPP-IV
Drug Design
General and cellular metabolism. Vitamins
Humans
Inhibitory Concentration 50
Medical sciences
Models, Molecular
Molecular Structure
Pharmacology. Drug treatments
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Pyrroles - chemistry
Pyrroles - pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship
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Summary:The cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of 5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor 53 exhibited a preferred PK/PD profile in preclinical animal models and was selected for additional profiling.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.10.063